Furans and method of production



Patented June 9, Q 1953 UNITED" srArss orrics FURANS AND METHOD or PRODUCTION Moses Wolf Goldberg, Upper Montclair, and Albert Israel Rachlin, Hackensack, N. J., assignors to Hoffmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application February 1, 1952, Serial N0. 269,618

This invention relates to 2-phenyl-5-(R- phenyl) furans, wherein R is a member of the group consisting of 4,5-dihydro-2-imidazolyl, l,5- dihydro-Mor 5)-lower alkyl-Z-imidazolyl and l,4,5,6-tetrahydro2-pyrimidyl radicals. The invention also encompasses the salts of the aforesaid compounds with acids, and the methods for preparing such compounds. The compounds, in

15 Claims. (Cl. 260251) the free base form, can be represented by the following general formula:

wherein R has the same meaning as hereinabove The latter is then treated with stannous chloride in the presence of concentrated hydrochloric acid and glacial acetic acid to form a 2 phenyl5 cyanophenyl-furan. The thus formed cyano substituted 2,5-diphenyl-furan is then reacted with a lower alkanol and hydrogen chloride to produce a 2-phenyl-5-[m-imino lower alkoxymethyDphenyllfuran hydrochloride. The latter is then reacted with a 1,2-diaminoor 1,3-diamino-alkane to form the 2-.(phenyD-5-(R- phenyhfurans comprising our invention. Thus, for example, when the 2-phenyl-5-[ic-imino lower alkoxymethyl)phenyllfuran hydrochloride is reacted with 1,2-diaminoethane, (ethylenediamine), a 2-phenyl-5-[(4,5 dihydro-2-imidaz- 'olyl) phenyllfuran is obtained. When a 1,2. d-i

amino lower alkyl substituted ethane is employed, e. g. i,2@diaminopropane, a 2 -phenyl-5-,[(4,5-dihydro-4 (or 5) lower alkyl-2 -imidazoly1) henyllfuran is produced, thelower alkyl group being in either the is or 5-position. When a 1,3-diamino alkane is employed, e. g. 1,3-diaminmpropane, a Z-phenyl 5-[(1,4,5,6 tetrahydro-Z- pyrimidyl) phenyllfuran is formed,

The Z-(phenyl) -5- (Rphenyl) furans are prelerably produced in the form of their hydrochlorides which readily crystallize.

The hy roch 0- rides can be readily converted into the free bases by treatmentfwith a suitable alkali; for example,

with an excess of sodium hydroxide solution;

Any suitable method may be employed in preparing salts, for example, the salts may be formed by adding the appropriate acid or acid agent, or a solution thereof, to a solution of the free base, and recovering the salt from the solvent.

The preparation of various intermediates employed in our process, which are new, is illustrated by the following examples.

' EXAMPLE A V p-cyanophenylglyoxal To amixture of 50000. of dioxane and 20 cc. of water were added 56 grams of finely divided selenium dioxide. The mixture was stirred at C. until the selenium dioxide had dissolved,

and. then 72.5 grams of p-cyanoacetophenone were added. The mixture was refluxed with stirring for 6 hours, during which time black metallic selenium precipitated. Stirring was continued without heating for 18 hours, and then the selenium was removed by filtration. The solvent was removed in vacuo and the hot residue was dissolved in 300 cc. of acetone. Theacetone was flashed off and the residue was distilledon an oil bath. The p-cyanophenylglyoxal was 'obtained as a heavy, viscous oil boiling at 104410 C.'/1.5-mm. A sample of the oily material-was converted to the hydrate by trituration with water. After several crystallizations from nitromethane, the white crystalline p-cyanopheriylglyoxal hydrate melted at96100 C.

EXAMPLE m-Ct anophenylglyoxal To a. mixture of 500 cc. of dioxane and 20 cc. of water were added 56 grams of finely divided selenium dioxide. The mixture was stirred at 50 C. until the selenium dioxide had dissolved,

and then 72.5 grams of m-cyanoacetophenone were added. .The mixture. was refluxed with stirring for 6 hours, during which time black metallic selenium precipitated. Stirring was continued without heating for 18 hours, and then the selenium was removed by filtration through a thin pad of activated charcoal. The solvent was, removed in vacuo, and the hot residue was dissolved. in 300 cc. of acetone. dashed off and the, residue was distilled on an oil bath. A heavy viscous oil boiling at l23-.-126

The acetone was 3 C. at 0.3 mm. was obtained. The hydrate prepared by treating the glyoxal with water was a white solid which melted at 54-5'7 C.

EXAMPLE C 1 -beneoyZ-2- (p-cyanobenzoyl) ethylene with 30 cc. of absolute ethanol, and then with r 30 cc. of ether. The yellow product thus obtained was recrystallized from 2,300 cc. of methanol, yielding ethylene, M. P. 143-145 C. in the form of yellow crystals.

f (2) A mixture of 6.7 grams of phenylglyoxal, 7.25 grams of p-cyanoacetophenone, and '1 cc. of

1-benzoyl-2- (p-cyanobenzoyl) I acetic anhydride was heated for 2.5 hours in an oil bath at 145-150 C. The reaction mixture was cooled at 4 C. for 24 hours. The mass which formed was filtered, and the product washed'with 20 cc. of absolute ethanol. 1-benzoyl-2-(p-cyanobenzoyDethylene was thus obtained having a M. P. of 141-143" 0.

EXAMPLE D 1 -benzoyZ-2- (m-cyanobenzoyl) ethylene (l) A mixture of 65.4 grams of m-cyanophenyl- 7 bath at 145150 C. Vacuum was applied to the hot mixture to remove the acetic acid formed, and after standing for '48 hours at room temperature, the mixture was triturated with 30 cc. of absolute ethanol, filtered, washed twice with 30 cc. of absolute ethanol, and then with 30 cc. of ether. The yellow product thus obtained was recrystallized from 1,200 cc. of methanol yielding l-benzoyl-Z- (m-cyanobenzoyl)ethylene, M. P. 126-127 C., in the form of yellow plates.

(2) A mixture of 15.2 grams of phenylglyoxal, 16.45 grams of m-cyanoacetophenone and cc. of aceticanhydride was heated for 2.5 hours in an oil bath at 145150 C. The reaction mixture was allowed to stand at room temperature for24 hours. The semi-solid mass thus obtained was 7 triturated with cc. of absolute ethanol, filtered,

washed with 15 cc. of absolute ethanol, and air dried. The crude product was recrystallized from 190 cc. of absolute ethanol, yielding 1-benzoyl-2- (m-cyanobenzoyl) ethylene, M. P. 126-127 C.

EXAMPLE E 2,-phenyZ-5- (m-cydnophenyl) fimm A mixture of 100 grams'of stannous chloride [dihydrate, 150 cc. of glacial acetic acid and 200 cc.

of concentrated hydrochloric acid were refluxed for 5 minutes. To the hot solution were added grams (0.096 mole) of l-benzoyl-Z-(m-cyanoben- "280 cc. of methanol, yielding 2-phenyl-5-(fl1- cyanophenyl) furan, M. P. 92.5-93 C.

EXAMPLE F 2-phenyl-5- (p-cyanophenyl) furan A mixture of grams of stannous chloride dihydrate, cc. of glacial acetic acid and 200 cc. of concentrated hydrochloric acid was refluxed for 5 minutes. To the hot solution were added 25 grams (0.096 mole) of lbenzoyl-2-(p-cyanobenzoyl) ethylene and the mixture was refluxed for 10 minutes; The reaction mixture was cooled to 5 C. and the product which had solidified was filtered. The filter cake was sucked dry and then washed with 500 cc. of cold water and air-dried.

The 2-phenyl-5-(p-cyanophenyl)furan thus obtained was crystallized from 575 cc. of methanol,

' M. P. 122-124" C.

The following examples will serve to illustrate the preparation of the 2-phenyl-5-(R-phenyl) furans, wherein R, has the meaning hereinabove assigned thereto. It will be understood that the invention is intended to embrace the compounds in their various tautomeric and isomeric forms, and the claims are to be thus construed.

EXAMPLE: 1

A solution of 5.7 grams (0.023 mole) of 2- phenyl-5-(m-cyanophenyl)furan in 25 cc. of chloroform and 1.2 cc. (0.03 mole) of methanol was cooled in an ice bath for 30 minutes. Anhydrous hydrogen chloride was passed into the cold solution for 7 minutes and the resulting darkcolored saturated solution was stored at about 4 C. for about 16 hours. The reaction mixture which now consisted of'a thick slurry of orange crystals was heated in vacuo to'50 C. in order to remove the chloroform. The residue was triturated with 125 cc. of ether and the solid was filtered with suction. The filter cake was washed three times with 75 cc. portions of ether. The resulting compound was 2-phenyl-5-[m(a-imino methoxymethyl) phenyl] -furan hydrochloride.

A mixture of 3.2 grams (0.01 mole) of 2-phenyl- 5 [m(a-iminomethoxymethyl)phenyllfuran hydrochloride, 20 cc. of ethanol and 0.78 cc. (0.012 mole) of anhydrous ethylenediamine was refluxed for six hours. The clear solution was allowed to crystallize at about 4 C. A first crop of crystals having a M. P. of 274276 C. was obtained. The mother liquor was evaporated to dryness and crystallization of the residue from 15 cc. of methanol yielded a second crop of crystals, M. P. 272-27 i C. The two crops were combined and recrystallized from 35 cc. of methanol containing 1 cc. of 25 per cent methanolic hydrogen chloride. The crystals were 2-phenyl-5- [m- (4,5-dihydro-2-imidazolyl) phenyllfuran hydrochloride, M. P. 276-278 C. They tend to retain methanol of crystallization. When crystallized from ethanol, the hydrochlo ride tends to retain ethanol of crystallization,

A methanol-water solution of 2-pheriyl-5- [m- (4,5-dihydro-2 -imidazolyl) phenyl furan hy drochloride was treated with an excess of sodium hydroxide solution to obtain the free base. Recrystallized from methanol, the white crystalline 2 phenyl 5 [m (4,5 dihydro 2 imidazo1yl phenyllfuran melted at 180-181 C. To 100 mg. of the free base dissolved in 3 cc. of methanol were added 3 drops of 85 per cent lactic acid. The solution was evaporated to dryness in vacuo and the residue was crystallized, first from ethanolether and then from acetonitrile. The lactate-salt thus obtained melted at 158-l60 'C. The hydrobromide, prepared in a similar manner from the retain water of crystallization. 287-288" 0.

It melts at EXAMPLE 2 colored saturated solution was stored at about 4 C. for about 16 hours. The reaction mixture was heated in vacuo at about 50 C. in order to remove the chloroform. The solid residue was triturated with 500 cc. of ether and the solid was filtered off with suction. The filter cake was washed with a total or 500 cc. of ether and air-dried. The cake consisted of 2-phenyl-5- [p (a iminomethoxymethyl) phenyllfuran hydrochloride.

A solution of 30.9 grams (0.099 mole) of 2- phenyl 5 [p (a iminomethoxymethyl) phenyllfuran hydrochloride, 210 cc. of ethanol and 8.5 cc. of anhydrous ethylenediamine (0.13 mole) was stirred and refluxed for six hours. Within minutes a crystalline solid started to appear and ammonia was liberated. The reaction mixture was cooled to about 4 C. and permitted to stand overnight. It was then filtered, washed with 25 cc. of cold ethanol and then 100 cc. of ether. Recrystallized from 700 cc. of methanol containing 25 cc. of 25 per cent methanolic hydrogen chloride, the 2-phenyl-5- [p (4,5 dihydro 2 imidazolybphenyllfuran hydrochloride thus obtained melted at 312-3l3 C. with decomposition.

A methanol-water solution of 2-phenyl-5- [p- (4,5-dihydro-2-imidazolyl) phenyll furan hydrochloride was treated with an excess of sodium hydroxide solution to obtain the free base. Recrystallized from methanol, the crystalline free base, 2-phenyl-5- [p- (4,5-dihydro-2-imidazoly1) phenyllfuran, melted at 203-204 C.

To a solution of 1.3 grams of 2-phenyl-5- [p- (4,5-dihydro-2-imidazolyl) phenyll furan dissolved in 15 cc. of warm methanol was added 0.55 cc. of 85 per cent lactic acid. The solution was evaporated to dryness in vacuo and the solid residue was recrystallized from 15 cc. of methanol and 10 cc. of ether. 2-phenyl5-[p-(4,5-dihydro- Z-imidazolyl) phenyllfuran lactate was obtained in the form of pale yellow crystals, M. .P. 197.5-198 C. l

. EXAMPLE 3 A mixture of 8.7 grams (0.028 mole) of 2- phenyl 5 [m (a iminomethoxymethyl) phenyllfuran hydrochloride, 50 cc. of ethanol,

and 2.7 cc. (0.034 mole) of 1,2-diaminopropane imidazolyDphenyl] furan, was dissolved in 25cc.

of ethanol, and 10 cc. of per cent ethanolic hydrogen chloride and 3 cc. of water were added. 90 cc. of ether were added to the alcoholic solution, and after cooling at 4 (3., Z-phenylethanol and ether, the compound melted at EXAMPLE 4 A mixture of 10.5 grams (0.0335 mole) of 2- phenyl 5 [p (a. iminomethoxymethyl) phenyllfuran hydrochloride, 50 cc. er ethanol, and 3.2 cc. (0.038 mole) of'l,2-diaminopropane was stirred and refluxed for 6 hours. The solution, after being cooled at 4 C. deposited a mass of yellow crystals. The product was filtered, washed with cold ethanol, and dried. After recrystallizationthree times'from alcohol, the 2- phenyl 5 -[p (4,5 dihydro 4(or '5)'methyl 2-imidazoly1)phenyl1furan hydrochloride obtained, M. P. 284-286 C.

EXAMPLE 5 A mixture of 5 grams (0.016 mole) of 2- phenyl 5 [m (a irninomethoxymethyl) phenyllfuran hydrochloride, 50 cc. of ethanol, and 2 cc. (0.024 mole) of l,3-diaminopropane was refluxed for 6 hours. The solution was poured into a mixture of 500 cc. of water and 50 cc. of 4 N sodium hydroxide solution, and the resulting precipitate was extracted into two 250 cc. portions of ether. The ether extracts were dried over sodium sulfate, the drying agent was washed thoroughly with chloroform, and the combined extracts were concentrated in vacuo. The solid yellow residue, 2-phenyl-5-[m(1,4,5,6- tetrahydro-Z-pyrimidyl)phenyllfuran, was dissolved in 40 cc. of ethanol andfi cc. of ethanolic.

hydrogen chloride. 160 cc. of ether were added to the alcoholic solution, and, after cooling at 40 C., 2-phenyl-5-[m-(1,4,5,6-tetrahydr0-2,-pyrimidyl)pheny1lfuran hydrochloride separated as a mass of almost white crystals. After filtration, drying and recrystallizing four times from ethanol ether, the compound melted at 235 C. A sample of the compound when mixed with 2-phenyl-5- [m- (4,5-dihydro-4 (or 5).methyl-2- imidazolyl) phenyllfuran hydrochloride melted at 213-218 C.

EXAMPLE 6 A mixture of 6.27 grams (0.02 mole) of 2- phenyl 5 [p (a iminomethoxymethyl) phenyllfuran hydrochloride, 70 cc. of ethanol, and 2.2 cc. (0.026 mole) of 1,3-diaminopropane was stirred and refluxed for 6 hours. The solvent was removed in vacuo and the solid residue was dissolved in cc. of ethanol. 20. cc. of ether were added and aftercooling at 40 C. the 2-phenyl-5-[p-(1,4,5,G-tetrahydro-Z-pyrimidyDphenyllfuran hydrochloride separated as a mass of white crystals. After being filtered,

washed with cool ethanol, dried, and recrystallized four times from moist ethanol-ether, the compound melted at 292-293" C.

This application is a continuation-inpart of our copending application Serial No. 197,492, filed on November 24, 1950.

We claim:

1. A compound of the class consisting of 2- phehy1-5-(R-phenyl)furans and the acid addition salts thereof, wherein R is a member of the group consisting of 4,5-dihydr0-2-imidazolyl, 4,5-dihydro C lower alkyl 2 imidazolyl, and 1,4,5,6-tetrahydro 2.-pyrimidyl radicals.

2. -2-phenyl-5-(R-phenyl) furans, wherein R is. 4,5-dihydro-2imidazolyl.

3. .2-phenyl-5-(R-phenyl)furans, wherein Ris 4,5-dihyd1o-C-lower alkyl-2-imidazolyl.

4. 2-phenyl-5-(R-phenyl) furans, wherein R is l,4,5,6-tetrahydro-2-pyrimidyl.

was

7 5. 2-phenyl-5-[m- (4, -dihydro-2-lmidazblyl) phenyl] furan hydrochloride.

6. 2-phenyl-5-[p (4,5-dihydro-2-imidazolyl) phenyllfuran hydrochloride.

'7. 2-phenyl-5- [m- (4,5-dihydro C methyl-2- imidazolyl) phenyl] furan hydrochloride;

8. 2 phenyl 5 [p-(4,5-dihydro-C-methy1-2- imidazolyl) phenyllfuran hydrochloride.

9. 2-phenyl-5-[m-(1,4,5,6 tetrahydro 2 pyrimidyl) phenyl] furan hydrochloride.

10. A process which comprises reacting a 2- phenyl-5-[(a-imino lower a-lkoxy methyl).phen yllfuran hydrochloride with a member of the group consisting of 1,2-diaminoand 1,3-diamino alkanes to form 2-phenyl-5-(R-phenyhfurans, wherein R is a member of the group con sisting of l,5-dihydro-2-imidazolyl, 4,5-dihydro- C-lower alkyl-Z-imidazolyl, and 1,4,5,6-tetrahy dro-Z-pyrimidyl radicals.

11. A process for producing 2-phenyl-5-[m- (4,5-dihydro-2-imidazolyl) phenyllfuran hydrochloride which comprises reacting 2-phenyl-5- [m-(a iminomethoxymethyl) phenyllfuran hydrochloride with ethylenediamine.

12. A process for producing 2-phenyl-5-[p- 8 (4,5 --dihydro-2-imidazolyl) phenyllfuran hydrochloride which comprises reacting 2-phenyl-5- [p (a iminomethoxymethyl) phenyllfuran hydrochloride with ethylenediamine.

13. A process for producing 2-phenyl-V5-[m- (4,5 dihydro C methyl-Z-imidazolyl) phenyllfura-n hydrochloride which comprises reacting Z-phenyl-B- [m (a iminomethoxymethyl) phenyllfuran hydrochloride with 1,2-diamino-propane.

14. A process for producing 2-phenyl-5-[p- (4,5 dihydro-C-methyl-2-imidazolyl) phenyllfuran hydrochloride which comprises reacting 2- phenyl-5- [p a iminomethoxymethyl) phenyl] :furan hydrochloride with 1,2-diaminopropane. v 15. A process for producing Z-phenyl-5-[m- (1,4,5,6 tetrahydro 2 pyrimidyl) phenyllfuran hydrochloride which comprises reacting 2-pheny1-5- [m- (a iminomethoxymethyl) phenyll furan hydrochloride with 1,3-diaminopropane.

MOSES WOLF GOLDBERG. ALBERT ISRAEL RACHLIN.

No references cited. 

1. A COMPOSITION OF THE CLASS CONSISTING OF 2PHENYL-5-(R-PHENYL) FURANS AND THE ACID ADDITION SALTS THEREOF, WHEREIN R IS A MEMBER OF THE GROUP CONSISTING OF 4,5-DIHYDRO-2-IMIDAZOLYL, 4,5-DIHYDRO - C - LOWER ALKYL - 2 - IMIDAZOLYL, AND 1,4,5,6-TETRAHYDRO-2-PYRIMIDYL RADICALS.
 10. A PROCES WHICH COMPRISES REACTING A 2PHENYL-5-((A-IMINO LOWER ALKOXY METHYL) PHENYLLFURAN HYDROCHLORIDE WITH A MEMBER OF THE GROUP CONSISTING OF 1,2-DIAMINO- AND 1,3-DIAMINO ALKANES TO FORM 2-PHENYL-5-(R-PHENYL) FURANS, WHEREIN R IS A MEMBER OF THE GROUP CONSISTING OF 4,5-DIHYDRO-2-IMIDAZOLYL, 4,5-DIHYDROC-LOWER ALKYL-2-IMIDAZOLYL, AND 1,4,5,6-TETRAHYDRO-2-PYRIMIDYL RADICALS. 